WO2024256849A1 - Dérivés d'acide 4-phénylbutyrique destinés à être utilisés en traitement de fibrose - Google Patents

Dérivés d'acide 4-phénylbutyrique destinés à être utilisés en traitement de fibrose Download PDF

Info

Publication number
WO2024256849A1
WO2024256849A1 PCT/IB2023/000354 IB2023000354W WO2024256849A1 WO 2024256849 A1 WO2024256849 A1 WO 2024256849A1 IB 2023000354 W IB2023000354 W IB 2023000354W WO 2024256849 A1 WO2024256849 A1 WO 2024256849A1
Authority
WO
WIPO (PCT)
Prior art keywords
fibrosis
phenylbutyric acid
acid derivative
treatment
day
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2023/000354
Other languages
English (en)
Inventor
Bernhard Ryffel
René Moser
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Phenotec Ag
Original Assignee
Phenotec Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Phenotec Ag filed Critical Phenotec Ag
Priority to PCT/IB2023/000354 priority Critical patent/WO2024256849A1/fr
Publication of WO2024256849A1 publication Critical patent/WO2024256849A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to 4-phenylbutyric acid derivatives for use in the treatment of fibrosis. It further relates to the 4-phenylbutyric acid derivatives for use in the treatment of interstitial lung disease and for use in the prevention of lung cancer.
  • Fibrosis is a pathological feature of many chronic diseases. Fibrosis is defined by the accumulation of excess extracellular matrix components. Fibrosis is similar to the process of scarring. Both involve stimulated fibroblasts laying down connective tissue, including collagen and glycosaminoglycans. Fibrosis is initiated when immune cells such as macrophages release soluble factors that stimulate fibroblasts.
  • a well-known pro-fibrotic mediator is TGF- ⁇ , which is released by macrophages as well as any damaged tissue between surfaces called interst it ium .
  • Other soluble mediators of fibrosis include connective tissue growth factor (CTGF) , platelet-derived growth factor (PDGF) , and interleukin 10 (IL-10) .
  • CTGF connective tissue growth factor
  • PDGF platelet-derived growth factor
  • IL-10 interleukin 10
  • Fibrosis can affect nearly every tissue in the body. Affected tissues in the body include lung tissue, liver tissue, kidney tissue, brain tissue, heart tissue, arterial tissue, tissue from joints, skin tissue, bone marrow tissue and gastrointestinal tissue.
  • Fibrosis occurs in the context of a wide variety of diseases and there are many different subtypes of fibrosis:
  • Scleroderma is an autoimmune rheumatic disease characterised by fibrosis in the skin and internal organs and by injuries to small arteries. It is a rare connective tissue disorder with unknown and complex pathogenesis. It can be divided into two forms, localised scleroderma, or systemic sclerosis, which can further be classified as either limited systemic sclerosis (formerly known as the CREST syndrome comprising of calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia) or diffuse systemic sclerosis based on clinical and serological criteria.
  • limited systemic sclerosis formerly known as the CREST syndrome comprising of calcinosis, Raynaud phenomenon, oesophageal dysmotility, sclerodactyly, and telangiectasia
  • diffuse systemic sclerosis based on clinical and serological criteria.
  • scleroderma Common treatments of scleroderma include medication to improve circulation, medicines that reduce the activity of the immune system and slow the progression of the condition, steroids to relieve joint and muscle problems, and moisturising affected areas of skin.
  • Skin fibrosis, or dermal fibrosis or cutaneous fibrosis is a symptom common to a number of diseases including scleroderma.
  • Causes include chemical exposure, trauma and irradiation. It is characterised by an increase of fibrous connective tissues in the dermis or subcutis. It is characterized by proliferation of fibroblasts and collagen fibres in the dermis or around hair follicles, typically oriented parallel to the epidermis. In more severe cases, the fibrosis can extend deeper into the dermis and subcutis. Corticosteroids, immunotherapy drugs, immunoglobulins, and anti-fibrotic drugs are commonly used in the treatment for cutaneous fibrosis.
  • Interstitial lung disease describes a large group of disorders, most of which cause progressive scarring of lung tissue.
  • the scarring associated with interstitial lung disease eventually affects your ability to breathe and get enough oxygen into the bloodstream.
  • High blood pressure in the lungs (pulmonary hypertension) , respiratory failure and right-sided heart failure are common consequences of ILD.
  • All interstitial lung diseases affect the lung interstitium, which is a lace-like network of tissue that goes through both lungs. It supports the lung' s tiny air sacs, called alveoli.
  • ILD interstitial pneumonia
  • idiopathic pulmonary fibrosis nonspecific interstitial pneumonitis
  • hypersensitivity pneumonitis hypersensitivity pneumonitis
  • cryptogenic organising pneumonia (COP) cryptogenic organising pneumonia
  • acute interstitial pneumonitis desquamative interstitial pneumonitis
  • sarcoidosis sarcoidosis and asbestosis.
  • ILD interstitial pneumonia
  • Inhalation of lung sensitising substances and particles can also be a cause of ILD.
  • These substances and particles include asbestos, bird excretions, coal dust, metal dust, grain dust, silica dust, pesticides, ozone and talc.
  • Some antibiotics, anti-inflammatory drugs, chemotherapy, radiotherapy and heart medications can also be the cause of ILD.
  • the treatment a patient receives depends on the type of ILD the patient has and its cause.
  • Antibiotics and antifungal drugs treat most interstitial pneumonias caused by bacteria and fungi, respectively.
  • Corticosteroids cause the immune system' s activity to slow, which can cause slowing down the course of the disease.
  • advanced ILD a lung transplant may be required.
  • Pulmonary fibrosis is one of many ILDs. In many cases, the exact cause of pulmonary fibrosis cannot be determined. In this case, the condition is called idiopathic pulmonary fibrosis. In other cases, the cause of pulmonary fibrosis is known.
  • the causes for pulmonary fibrosis are the same as for ILD in general mentioned above. It can also be caused by a number of conditions including dermatomyositis, polymyositis, mixed connective tissue disease, systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, scleroderma and pneumonia.
  • the influences described can lead to cell death with destruction of the alveolar wall leading to emphysema, fibroblast activation and proliferation. This results in TGF- ⁇ driven fibre and matrix deposition, defective alveolar cell repair and severe fibrosis.
  • pulmonary fibrosis As pulmonary fibrosis progresses, it may lead to complications such as blood clots in the lungs, a collapsed lung or lung infections. Also, the risk of developing lung cancer is increased in pulmonary fibrosis patients.
  • Comorbidity is the presence of one or more additional conditions often co-occurring with a primary condition.
  • the additional condition (s) can be the cause of the primary condition, or the addi- tional condition ( s ) can be caused by the primary condition, or the conditions exist simultaneously regardles s of their causal relationship . In the last case , the conditions might have a common cause .
  • Typical comorbidities of pulmonary fibrosis , and idiopathic pulmonary fibrosis in particular, are pulmonary hypertension and acute exacerbation .
  • the treatment options for all types of fibrosis and diseases as sociated with fibrosis as described are extremely limited and there is a great need for new treatment s that can at least alleviate the symptoms and signs arising from fibrosis and/or that can prevent fibrosis at least partially from developing .
  • the sodium salt of 4-phenylbutyric acid, sodium 4-phenylbutyrate is used in the treatment of urea cycle disorders .
  • it has also been described in patent s and in the scientific literature for a number of medical uses . These uses encompas s a variety of illnes ses , such as benign prostatic hyperplasia, cancer, HIV, kidney failure and thalassemia .
  • WO 9510271 A2 discloses compositions and methods using 4-phenylbutric acid derivatives for therapy and prevention of a number of pathologies .
  • EP 25997 67 Al ( LUNAMED AG, 05 June 2013 ) describes a number of 4-phenylbutric acid derivatives for use in cancer therapy and other pharmaceutical applications .
  • EP 238 9932 Al ( LUNAMED AG, 30 November 2011 ) refers to pharmaceutical compositions comprising the histone hyperacetylating agent phenylbutyric acid for use in the treatment of a genetic disorder, like treatment of depres sion, vaginitis and varicosis or the prevention of Sudden Infant Death Syndrome with a genetic disorder background .
  • the 4-phenylbutyric acid derivatives N- (4-phenylbutanoyl-D- alanine) (Formula 1.1) and N- ( 4-phenylbutanoyl-L-alanine ) (Formula 1.2) have been found to be effective in the treatment of bowel diseases in EP 3283066 Bl (PHENOTEC AG, 11 May 2022) .
  • Diseases treatable with the 4-phenylbutyric acid derivatives of Formula 1.1 and/or Formula 1.2 comprise Crohn's disease, ulcerative colitis, inflammatory diseases of the bile ducts, vulvovaginitis, varicose veins, major depressive disorder and tinnitus .
  • a first aspect of the invention relates to a 4-phenylbutyric acid derivative, namely:
  • N- ( 4-phenylbutanoyl-D-alanine ) (Formula 1.1) ; and/or N- ( 4-phenylbutanoyl-L-alanine ) , (Formula 1.2) or pharmaceutically acceptable salts, solvates and/or hydrates thereof for use in the treatment of fibrosis.
  • the above-mentioned 4-phenylbutric acid derivatives may be employed as a single stereoisomer or as a mixture of stereoisomers. Such stereoisomers can be enantiomers.
  • the compounds may be used as a racemate. However, preferably they are used in en- ant iomerically pure form.
  • the 4-phenylbutric acid derivatives may be employed in form of the free acid, the free base, as a salt, as a solvate, or as a hydrate.
  • the term "pharmaceutically acceptable salt” is used to refer to an ionisable active pharmaceutical ingredient (API) that has been combined with a counterion to form a neutral complex.
  • a pharmaceutically acceptable salt is a salt of an API that is clinically equivalent to the API, meaning that the addition of the counterion of the resulting salt does not lead to clinically severe adverse events; or substantially the same maximum venous blood serum concentration, c max , is achieved; or it takes substantially the same time until the maximum venous blood serum concentration is reached, t max ; or the area under the curve, AUC, based on venous blood serum concentration as a function of time is substantially the same; or the API and its salt have substantially the same partition coefficient, log P; or the API and its salt have substantially the same dissociation constant, pK a ; or the API and its salt have substantially the same melting point; or any combination of these conditions.
  • pharmaceutically acceptable salts comprise salts of the compounds in Formula 1.1 and Formula 1.2 with a counterion selected from the group consisting of aluminium, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamine, zinc, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, ede- tate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate,
  • a solvate of a compound is the crystal structure of said compound where a solvent is incorporated into the lattice.
  • a pharmaceutically acceptable solvate is a solvate of an API that is clinically equivalent to the API, meaning that the solvent incorporated into the lattice does not lead to clinically severe adverse events; or substantially the same maximum venous blood serum concentration, c max , is achieved; or it takes substantially the same time until the maximum venous blood serum concentration is reached, t max ; or the area under the curve, AUC, based on venous blood serum concentration as a function of time is substantially the same; or the API and its solvate have substantially the same melting point; or any combination of these conditions.
  • pharmaceutically acceptable solvates comprise solvates of the compounds in Formula 1.1 and Formula 1.2 with an incorporated solvent selected from the group consisting of H 2 0, ethanol, DMSO, propanediol, acetone, 1 -propanol, isopropanol or any combination thereof.
  • a pharmaceutically acceptable hydrate is a pharmaceutically acceptable solvate, wherein H 2 0 is the solvent incorporated into the crystal lattice.
  • a treatment of a disease refers to an effect as a result of the administration of a compound to a living organism, wherein the effect is the prevention or delay of onset of symptoms; or amelioration of symptoms; or prevention or delay of onset of signs; or amelioration of signs; or a combination thereof.
  • a symptom is something felt or experienced, such as pain or dizziness.
  • a sign is an objective observable indication of a disease, injury, or abnormal physiological state that may be detected during a physical examination, examining the patient history, or diagnostic procedure.
  • Disease biomarkers are a type of sign. Signs and symptoms are not mutually exclusive.
  • these symptoms and signs comprise shortness of breath (dyspnoea) , a dry cough, fatigue, unintended weight loss, aching muscles (myalgia) , aching joints (arthralgia) , widening and rounding of the tips of the fingers and/or toes (clubbing) , the presence of fibrosis biomarkers, histopathological confirmation of the presence of fibrotic tissue, spiromet rical confirmation of reduced forced ex- piratory volume in 1 second (FEV1 ) , and spirometrical confirmation of reduced forced vital capacity (FVC ) .
  • Organs where fibrotic tis sue can form include the lungs , heart , liver, skin, cardiovascular ves sels , brain, gastrointestinal tract , bone marrow and kidneys .
  • the 4-phenylbutyric acid derivatives described in the present invention exert their ef fect at a point in the biochemical cascade of formation of fibrosis , which plays a role in all types of fibrosis or at least in most types of fibrosis .
  • 4-phenylbut ric acid derivatives according to the invention are physiologically well tolerated .
  • the fibrosis is accompanied by scleroderma .
  • scleroderma is an autoimmune rheumatic disease .
  • it can comprise development of fibrosis of the skin and other organs such as the lung .
  • Another preferred embodiment relates to the 4-phenylbutyric acid derivative according to the first aspect of the present invention for use in the treatment of skin fibrosis .
  • a second aspect of the present invention relates to a 4- phenylbutyric acid derivative, namely:
  • interstitial lung disease comprises several disorders causing progressive scarring of lung tissue. It has been found that the compound (s) according to the invention can be used for the treatment of said progressive scarring of lung tissue.
  • a preferred embodiment relates to the 4-phenylbutyric acid derivative according to the first and/or second aspect of the present invention for use in the treatment of pulmonary fibrosis.
  • the treatment reduces the number of dead epithelial cells in the bronchoalveolar lavage (BAL) accompanied by a reduction in total protein and DNA.
  • BAL bronchoalveolar lavage
  • the treatment leads to a significant reduction of macrophages and neutrophils and concomitant myeloperoxidase in the BAL. Therefore, the treatment reduces the acute respiratory barrier injury that can be induced by certain chemotherapeutic agents, for example. Acute respiratory barrier injury results often in the development of fibrotic tissue during the repair process.
  • the treatment reduces the typical biomarkers of lung fibrosis.
  • biomarkers include TGF- ⁇ in the BAL, IL-l ⁇ in the BAL fluid (BALF) , IL-6 in the BALF, TIMP-1 in the BALF, MMP-9 in the BALF, and collagen in the BAL.
  • histological data indicate the reduction of lung emphysema and a reduction in the formation of fibrotic tissue.
  • Another preferred embodiment relates to the 4-phenylbutyric acid derivative according to the first and/or second aspect of the invention for use in the treatment of idiopathic pulmonary fibrosis ( IPF ) .
  • idiopathic pulmonary fibrosis If the cause of the development of fibrotic tissue in the lung is unknown, the condition is called idiopathic pulmonary fibrosis.
  • a further preferred embodiment relates to the 4-phenylbutyric acid derivative according to the first and/or second aspect of the invention for use in the treatment of pulmonary fibrosis, wherein the pulmonary fibrosis is induced by chemotherapeutic agents and/or by radiotherapy, in particular by chemotherapeutic agents selected from the group consisting of bleomycin, mitomycin C, busulfan, cyclophosphamide, chlorambucil, melphalan, methotrexate, 6-mercaptopurine, azathioprine, cytosine arabinoside, gemcitabine, fludarabine, bis (chloroethyl) nitrosourea, chloroethyl cyclohexyl nitrosourea, methyl chloroethyl cyclohexyl nitrosourea, etoposide, paclitaxel, docetaxel, all-trans retinoic acid, gefitinib, imatinib mes
  • Radiotherapy cancer therapy can result in tissue damage known as radiation fibrosis.
  • chemotherapeutic agents have been associated with pulmonary toxicities.
  • One of the effects of those agents can be the development of severe fibrosis in the lungs resulting in respiratory insufficiency and possibly death (LIMPER, A. H. Chemotherapy-induced lung disease. Clin. Chest. Med. 2004, Vol. 25, pages 53-64) .
  • LIMPER A. H. Chemotherapy-induced lung disease. Clin. Chest. Med. 2004, Vol. 25, pages 53-64
  • the 4-phenylbutyric acid derivatives according to the invention can attenuate the adverse effects of such chemotherapeutic agents .
  • a yet further preferred embodiment relates to the 4- phenylbutyric acid derivative according to the first and/or second aspect of the present invention, wherein the pulmonary fibrosis or idiopathic pulmonary fibrosis is accompanied by pulmonary hypertension as a complication.
  • Another preferred embodiment relates to the 4-phenylbutyric acid derivative according to the first and/or second aspect of the present invention for use in the treatment of the syndrome of combined pulmonary fibrosis and emphysema (CPFE) .
  • CPFE combined pulmonary fibrosis and emphysema
  • Emphysema the presence of air-filled spaces caused by the breakdown of the walls of the alveoli, is relatively common in patients with fibrotic ILD.
  • the co-occurrence of these conditions is known as the syndrome of CPFE.
  • a further preferred embodiment relates to the 4-phenylbutyric acid derivative according to the first and/or second aspect of the present invention, wherein the pulmonary fibrosis or idio- pathic pulmonary fibrosis is accompanied by acute exacerbation as a complication.
  • Acute exacerbation is a sudden worsening of symptoms of pulmonary diseases. Those symptoms include shortness of breath and increased amount of phlegm.
  • a preferred embodiment relates to the 4-phenylbutyric acid derivative according to the first and/or second aspect of the present invention, wherein fibrosis formation occurs on an inflammat ion-independent immune pathway.
  • a third aspect of the present invention relates to a 4- phenylbutyric acid derivative, namely:
  • Lung cancer is an important comorbidity encountered in ILD patients, especially in pulmonary fibrosis patients. Although the causal relationship between lung cancer and ILD is not yet com- pletely understood, the scientific literature suggest s that ILD may promote lung cancer development . Specifically in IPF , some molecular and genetic features of it s pathogenesis and progression are linked to mechanisms that favour development of malignancy (KEWALRAMANI , N . et al . Lung cancer in patient s with fibrosing ILDs , ERJ Open Res . 2022 , Vol 8 , 00115-2022 ) .
  • the 4-phenylbutyric acid derivatives according to the invention are suitable for reducing the risk of lung cancer .
  • a preferred embodiment relates to the 4-phenylbutyric acid derivative according to any one aspect of the present invention, wherein the treatment is a preventive and/or curative treatment , wherein the 4-phenylbutyric acid derivative is administered at a dose of between 1 mg/kg/day and 500 mg/kg/day, preferably between 10 mg/kg/day and 200 mg/kg/day, more preferably between 20 mg/kg/day and 200 mg/kg/day, and most preferably 30 mg/kg/day .
  • a preventive treatment is a treatment , wherein an active pharmaceutical ingredient (AP I ) is administered prior to onset of symptoms and/or signs of a particular disease to reduce the risk of developing that disease or prevent that disease entirely .
  • the AP I may be administered as a preventive measure .
  • I f for example , a patient is treated with a chemotherapeutic agent that can induce the development of fibrotic tissue , the 4-phenylbutyric acid derivatives according to the invention can be administered to prevent development of fibrosis .
  • a curative treatment is a treatment, wherein an API is administered after onset of symptoms and/or signs of a particular disease to prevent or slow down the development of the disease.
  • a dose of, for example, 30 mg/kg/day indicates that, within one day, an amount of 30 mg of the API is administered per kg bodyweight of the subject.
  • Another preferred embodiment relates to the 4-phenylbutyric acid derivative according to any one aspect of the present invention, wherein the 4-phenylbutyric acid derivative is administered
  • the medicament of the present invention may for example be administered partially in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
  • conventional pharmaceutical recipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions.
  • These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the compositions may take any convenient form, such as tablets, pellets, granule, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions or dry powdered forms suitable for reconstitution with water or other suitable liquid media before use.
  • the multiparticulate forms such as pellets or granules, may be filled into a capsule , compres sed into tablet s or suspended in a suitable liquid .
  • suitable controlled release formulations and methods for their preparations are known from the prior art .
  • the dosage form depends in particular on the disease to be treated .
  • oral or intravenous administration is suitable if pulmonary fibrosis is to be treated.
  • acces s to the active substance via the blood capillaries may pos sibly be hindered .
  • a transdermal patch applied on the chest of a sub j ect is suitable in such a case , for example , whereby the active substance can reach the lung tis sue through the skin .
  • the aim of the following implementation examples was to test the pharmacological ef ficacy of APB in the mouse model of bleomycin (BLM) -induced lung fibrosis by daily gavage for up to 14 days .
  • Pulmonary fibrosis is modelled experimentally by a single intratracheal administration of bleomycin (BLM; 1 . 5 mg/kg) in 8 weeks to 10 weeks old C57BI mice characterised by an acute in jury of the alveolar epithelium followed by emphysema, repair and lung fibrosis .
  • APB powder was dissolved in physiological saline and administered in a volume of 200 ⁇ l per gavage.
  • mice were observed daily for clinical signs and adverse effects and body weights were recorded before each gavage to adjust the APB dose.
  • mice were sacrificed at day 15 for full analyses:
  • Bronchoalveolar lavage was performed by rinsing the lungs four times with 0.5 ml physiological saline solution at room temperature. After centrifugation at 400 g for 10 min at 4 °C, the supernatant (cell-free BAL fluid) was stored at -20 °C for cytokine analysis. The total cells were counted and differential cell counts were assessed on Giemsa stained cytospins .
  • Cytokines measurement in BALF Levels of CXCL1, IL-l ⁇ , IL-6, TIMP-1, MMP-9 and MPO in BALF were determined by enzyme-linked immunosorbent assay (ELISA) , using commercial kits from R&D (Abingdon, UK) . Total protein, DNA and collagen levels were assessed by Sircol assay as described before (BESNARD, A.-G. et al. CXCL6 antibody neutralization prevents lung inflammation and fibrosis in mice in the bleomycin model. J. Leukoc. Biol. 2013, Vol. 94, p. 1317-1323) .
  • mice Microscopic analyses of lungs: The right lungs were fixed in 4 % buffered paraformaldehyde, processed, embedded in paraffin, cut at 3 pm and stained with haematoxylin and eosin. The microscopic slides were analysed for morphological alterations, assessed by a semi-quantitative score 0-5 (with increasing severity) as described (FANNY, M. et al. The IL-33 Receptor ST2 Regulates Pulmonary Inflammation and Fibrosis to Bleomycin. Front. Immunol. 2018, Vol. 9, p. 1-12) . The left lung was frozen at -80° for potential future analyses.
  • Fig. la-lf Treatment with APB (N- ( 4-phenylbutanoyl-D- alanine) ) attenuates the BLM-induced cell recruitment in bronchoalveolar lavage (BAL) .
  • Mice were challenged by a single intratracheal administration of bleomycin in saline (BLM;
  • mice 1.5 mg/kg and were treated with or without APB at 10 mg/kg, 30 mg/kg, or 100 mg/kg daily for 14 days, control mice received int rat racheally the vehicle only. Eight mice/group, mean and SD .
  • Fig. 2a-2f Treatment with APB attenuates the BLM-induced increased cytokine levels in the bronchoalveolar fluid (BALF) .
  • BALF bronchoalveolar fluid
  • BLM bleomycin
  • mice received intratracheally the vehicle only. Eight mice/group, mean and SD .
  • Fig. 3a-3g Treatment with APB attenuates lung fibrosis by microscopy. After a single intratracheal instillation BLM daily APB at 10 mg/kg, 30 mg/kg, or 100 mg/kg for 14 days mice were analysed at day 15. Control mice received intratracheally the vehicle only. Eight mice/group, mean and SD .
  • Fig. 4a-4f Curative treatment with APB attenuates the emphysema and fibrosis of the lungs. After an intratracheal instillation of bleomycin (BLM) the mice received from day 7 APB daily at 30 mg/kg and were analysed at day 14. Control mice received intratracheally the vehicle only. Six mice/group, mean and SD .
  • Example 1 Reduction of BLM-induced cell recruitment
  • mice with BLM-induced pulmonary fibrosis were treated with APB (N- ( 4-phenylbutanoyl-D-alanine ) ) at 10 mg/kg/day, 30 mg/kg/day, or 100 mg/kg/day for 14 days.
  • APB 4-phenylbutanoyl-D-alanine
  • the mice were followed daily for clinical adverse effects. Body weight was taken before compound administration. At day 15, the mice were sacrificed for inflammatory cells recruitment and microscopic analysis.
  • Fig. 1 shows levels of biomarkers for acute respiratory barrier injury of the control group (C) , the group that received BLM only (BLM) and the groups that received both BLM and APB at varying doses (10 mg/kg APB per day: BLM+APB10; 30 mg/kg APB per day: BLM+APB30; 100 mg/kg APB per day: BLM+APB100) , after 14 days.
  • the total cells in the BAL (Fig. la; xlO 4 ) , the number of neutrophils in the BAL (Fig. lb; xlO 4 ) , the number of macrophages in the BAL (Fig. lc; xlO 5 ) , the number of lymphocytes in the BAL (Fig. Id; xlO 4 ) , the DNA in the BAL (Fig. le; ng/ml) and the total protein in the BAL (Fig. If; pg/ml) were measured.
  • test compound APB was given daily by gavage at 0 mg/kg/day, 10 mg/kg/day, 30 mg/kg/day and 100 mg/kg/day for 14 days. APB at 100 mg/kg/day was well tolerated. No clinical adverse effects related to the administration of the test compound was observed.
  • mice with BLM-induced fibrosis were treated with APB at doses of 10 mg/kg/day, 30 mg/kg/day and 100 mg/kg/day for 14 days. Biomarkers indicative for pulmonary fibrosis were measured after 14 days.
  • Fig. 2 shows levels of biomarkers for fibrosis of the control group (C) , the group that received BLM only (BLM) and the groups that received both BLM and APB at varying doses (10 mg/kg APB per day: BLM+APB10; 30 mg/kg APB per day: BLM+APB30; 100 mg/kg APB per day: BLM+APB100) , after 14 days.
  • CXCL1 in the BALF Fig. 2a; pg/ml
  • IL-l ⁇ in the BALF
  • Fig. 2b pg/ml
  • IL-6 in the BAL
  • Fig. 2c pg/ml
  • TIMP-1 in the BALF
  • Fig. 2d pg/ml
  • MMP-9 in the BALF
  • Fig. 2e ng/ml
  • collagen in the BAL Fig. 2f; pg/ml
  • BLM leads within 14 days to increased cytokine production such as TGF- ⁇ , IL-l ⁇ , IL-6, TIMP-1, MMP-9, and collagen levels in the BALF, which are involved in the fibrotic disease process in mice.
  • APB had a dose dependent effect on CXCL1, IL-l ⁇ , IL-6 levels.
  • the remodelling factors TIMP-1 and MMP-9 as well as collagen were reduced by APB in the BALF.
  • Example 3 Reduction of lung emphysema and pulmonary fibrosis
  • the lung tissue of the mice in example 2 was analysed histologically after 14 days.
  • Fig. 3a-e show histological images of the lung tissue of the control group (C) , the group that received BLM only (BLM) and the groups that received both BLM and APB at varying doses (10 mg/kg APB per day: BLM+APB10; 30 mg/kg APB per day:
  • Fig. 3f shows an emphysema score determined from the histological images
  • Fig. 3g shows a lung fibrosis score determined from the histological images.
  • Fig. 4 shows levels of biomarkers for fibrosis, the lung fibrosis score and the emphysema score of the control group (C) , the group that received BLM only (BLM) and the group that received both BLM and APB (BLM+APB30; APB treatment starting at day 7) , after 14 days.
  • TIMP-1 in the BALF Fig. 4a; pg/ml
  • MMP-9 in the BALF Fig. 4b; ng/ml
  • collagen in the BAL Fig. 4c; pg/ml
  • lung fibrosis score Fig. 4d; a.u.
  • emphysema score Fig. 4e; a.u.
  • collagen in the lung Fig. 4f; pg/ml
  • APB is an effective treatment by either preventive or curative administration in the murine fibrosis model.
  • examples 1-4 demonstrate that the daily oral administration of APB at has a dose-dependent preventive and curative effect attenuating lung fibrosis in the BLM mouse model of lung fibrosis .

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des dérivés d'acide 4-phénylbutyrique, à savoir les composés N-(4-phénylbutanoyl-D-alanine) et/ou N-(4-phénylbutanoyl-L-alanine), destinés à être utilisés dans le traitement d'une fibrose. L'invention concerne en outre lesdits dérivés d'acide 4-phénylbutyrique destinés à être utilisés dans le traitement d'une maladie pulmonaire interstitielle et destinés à être utilisés dans la prévention du cancer du poumon.
PCT/IB2023/000354 2023-06-13 2023-06-13 Dérivés d'acide 4-phénylbutyrique destinés à être utilisés en traitement de fibrose Ceased WO2024256849A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2023/000354 WO2024256849A1 (fr) 2023-06-13 2023-06-13 Dérivés d'acide 4-phénylbutyrique destinés à être utilisés en traitement de fibrose

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2023/000354 WO2024256849A1 (fr) 2023-06-13 2023-06-13 Dérivés d'acide 4-phénylbutyrique destinés à être utilisés en traitement de fibrose

Publications (1)

Publication Number Publication Date
WO2024256849A1 true WO2024256849A1 (fr) 2024-12-19

Family

ID=87245694

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2023/000354 Ceased WO2024256849A1 (fr) 2023-06-13 2023-06-13 Dérivés d'acide 4-phénylbutyrique destinés à être utilisés en traitement de fibrose

Country Status (1)

Country Link
WO (1) WO2024256849A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010271A2 (fr) 1993-10-12 1995-04-20 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Phenylacetate et ses derives seuls ou associes a d'autres composes pour traiter des neoplasmes et d'autres troubles
EP2389932A1 (fr) 2010-05-28 2011-11-30 Lunamed AG Compositions à utiliser dans les troubles génétiques comportant un acide butyrique 4 phényl et ses sels
EP2599767A1 (fr) 2011-11-30 2013-06-05 Lunamed AG Dérivés de phénylbutyl
WO2016165770A1 (fr) * 2015-04-16 2016-10-20 Peter Truog Dérivés d'acide 4-phénylbutyrique
WO2019197015A1 (fr) * 2018-04-09 2019-10-17 Peter Truog Composition comprenant des dérivés d'acide 4-phénylbutyrique et des opioïdes

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010271A2 (fr) 1993-10-12 1995-04-20 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Phenylacetate et ses derives seuls ou associes a d'autres composes pour traiter des neoplasmes et d'autres troubles
EP2389932A1 (fr) 2010-05-28 2011-11-30 Lunamed AG Compositions à utiliser dans les troubles génétiques comportant un acide butyrique 4 phényl et ses sels
EP2599767A1 (fr) 2011-11-30 2013-06-05 Lunamed AG Dérivés de phénylbutyl
WO2016165770A1 (fr) * 2015-04-16 2016-10-20 Peter Truog Dérivés d'acide 4-phénylbutyrique
EP3283066B1 (fr) 2015-04-16 2022-05-11 Phenotec AG Dérivés d'acide 4-phénylbutyrique
WO2019197015A1 (fr) * 2018-04-09 2019-10-17 Peter Truog Composition comprenant des dérivés d'acide 4-phénylbutyrique et des opioïdes

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BESNARD, A.-G. ET AL.: "CXCL6 antibody neutralization prevents lung inflammation and fibrosis in mice in the bleomycin model", J. LEUKOC. BIOL., vol. 94, 2013, pages 1317 - 1323
FANNY, M. ET AL.: "The IL-33 Receptor ST2 Regulates Pulmonary Inflammation and Fibrosis to Bleomycin", FRONT. IMMUNOL.
KEWALRAMANI, N. ET AL.: "Lung cancer in patients with fi-brosing ILDs", ERJ OPEN RES, vol. 8, 2022, pages 00115 - 2022
LIMPER, A. H.: "Chemotherapy-induced lung disease", CLIN. CHEST. MED., vol. 25, 2004, pages 53 - 64
LO RE, S. ET AL.: "Uncoupling between Inflammatory and Fibrotic Responses to Silica", PLOS, vol. 9, no. 7, 2014, pages 1 - 10
T.A. GUDASHEVA ET AL.: "Design and synthesis of cholecystokinin-4 dipeptide analogues with anxiolytic and anxio genic activities", RUSS. J. BIOORGANIC CHEM., vol. 33, 2007

Similar Documents

Publication Publication Date Title
US12318361B2 (en) Methods for treating cardiovascular diseases
ES2792064T3 (es) Uso de glutaril histamina para tratar infecciones de las vías respiratorias
TWI656874B (zh) 西羅莫司或其藥學上可容許的鹽之用途
EP2938339B1 (fr) Traitement de la rhinosinusite par des inhibiteurs de glycoprotéine p
ES2679279T3 (es) Composiciones farmacéuticas inyectables para el tratamiento de las articulaciones
ES2383005T3 (es) Medicamentos para enfermedades glomerulares
JP2001519392A (ja) シクロスポリンおよびタクロリムスによって起こる腎臓毒の防止方法
KR20210018906A (ko) Anca 연관 혈관염에 대한 c5a 길항제의 투여 및 효과
PT2120919E (pt) Nova combinação para utilização no tratamento de perturbações inflamatórias
WO2024256849A1 (fr) Dérivés d'acide 4-phénylbutyrique destinés à être utilisés en traitement de fibrose
WO2009052630A1 (fr) Compositions et procédés permettant de traiter des troubles fibroprolifératifs
KR20080108156A (ko) 유기 화합물의 조합물
RU2012140396A (ru) Гиперсульфатированные глюкопиранозиды
EA002058B1 (ru) Новые соли врс-пептидов с органопротективной активностью, способ их получения и их использование в терапии
JP2022530732A (ja) Ｎｅｔ関連合併症を処置及び予防するための化合物
EP2934552A2 (fr) Méthode de traitement de l'insuffisance cardiaque diastolique par inhibition de la galectine-3
JP6040223B2 (ja) 放射線緩和剤および放射線保護剤としてのｂｐｉおよびその同類物
WO2022051316A1 (fr) Combinaisons à dose fixe de chs-131 et d'un inhibiteur de sglt-2
CA3048494C (fr) Methodes de traitement des maladies cardiovasculaires
RU2451507C2 (ru) Лекарственное средство для лечения хронического обструктивного заболевания легких
US20230041980A1 (en) Method of protecting a respiratory tract or a lung from damage, method of protecting a lung from pressure damage induced by a ventilator, method of suppressing spread of infection with viruses or bacteria that cause pneumonia in pulmonary bronchial epithelial cells or alveolar epithelial cells, and nasal spray
KR20250101963A (ko) 이나보글리플로진을 유효성분으로 포함하는 원형 탈모 예방 또는 치료용 약학 조성물
KR20240168338A (ko) 호흡기 질환 치료제
CN120605268A (zh) 化合物clt-28643在制备防治肺纤维化药物中的应用
HK40048339A (en) Treatment of rhinosinusitis with p-glycoprotein inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23741116

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE